8(9 10)-abeo-steroids

ABSTRACT

8(9$10)-ABEO-STERIODS AND THEIR 3-ENOLACYLATES, ACTIVE AS ANTI-ANDROGENS.

United States Patent Oifice US. Cl. 260-488 B 5 Claims ABSTRACT OF THEDISCLOSURE 8[9 10]-abeo-steroids and their 3-enolacylates, active asanti-androgens.

BACKGROUND OF THE INVENTION Jeger and his co-Workers [Helv. Chem. Acta,51, 1362 (1968)] have discussed the photolysis of6a,7a-oxidoandrosta-4,5 (6 -dien- 17 B-hydroxy-3-onel7-acetate.

SUMMARY This invention provides a process for preparing 8[910]-abeo-steroids and their 3-enolacylates according to the followingequation:

AeO

III

Wherein Rand R, when taken singly, are chosen from the group pairsconsisting of hydrogen and hydroxyl, ethinyl and hydroxyl, vinyl andhydroxyl, methyl and hydroxyl, ethyl and hydroxyl, propyl and hydroxyl,and acetyl and hydrogen and, when taken together are a carbonyl group,and

Wherein Ac is a lower alkanoyl group such as acetyl, propionyl, butyryl,formyl or isobutyryl.

In carrying out the first step of the above reaction sequence the 90:, aoxide (I) is irradiated with ultraviolet light in an inert solvent.Ultra-violet light having a wave length of 2537 A is preferred. Usefulinert solvents for the irradiation reaction include high-boilingalcohols or ketones and t-butanol has been a particular useful solventfor the irradiation. The 8[9 10]-abeo-steroid (II) is converted to thecorresponding 3-enolacylate (III) by treatment with an acylating agentsuch as an anhydride to which a catalytic quantity of perchloric acidhas been added or by using a mixture of the anhydride and thecorresponding aeyl chloride. The reaction producing the enolacylate isterminated after a reaction time of from 3 to 7 minutes, since longerreaction times produce undesirable by-products.

The compounds of this invention are anti-androgens. For example, 3,175dihydroxy 8[9- 10] abeo estra- 3,5-diene 9-0ne-diacetate in a standardtest is a 25 percent or better inhibitor of the androgenic stimulationof the 3,631,093 Patented Dec. 28, 1971 growth of seminal vesicles,ventral prostates and levator ani muscles, as measured by their weightswhen compared with the weights of organs from untreated control animals.17p hydroxy 17a ethinyl 8[9- 10] abeoestr-4-ene-3,9-dione also has shownanti-androgenic activity in the same standard tests. The compounds ofthis invention are active as anti-androgens in dosage ranges from 0.5 to5 mg. and can be administered to animals in the same dosage forms as areutilized for administration of steroid androgens or other steroidhormones.

This invention is also further illustrated by the following specificexamples:

EXAMPLE I 17/3-hydroxy-8 [9 10]-abeo-estr-4ene-3,9-dione One andone-half grams of 9a,10u-oxido-estr-4-ene- 17,8-ol-3-0ne were dissolvedin 750 ml. of t-butanol and the resulting solution Was irradiated for2.5 hours with ultra-violet light at 2537 A. The irradiation was carriedout under a nitrogen atmosphere in a quartz photo-chemical reactor using16 R.P.R. 2537 A lamps as a light source. A 70 percent yield of 17 3hydroxy 8[9- 10] abeoestr-4-ene-3,9-dione was obtained after removal ofthe solvent in vacuo and separation of the abeo-steroid product from thestarting material by chromatography over silica-gel (60-200 mesh). 17Bhydroxy 8[9- 10] abeoestr-4-ene-3,'9-dione has the following properties:M.P.= 215-216 C. after recrystallization from acetone.

Infra-red spectrum showed carbonyl peaks at 1685 CHI-1, using chloroformas a solvent.

Ultra-violet spectrum showed a maxima at 233 m (e=13,350, in ethanol.)

Nuclear magnetic resonance spectrum in deutrochloroform showed signalsat 5.72 ppm. and 0.90 ppm.

Mass spectrum peaks were found at m/e=288 (molecular ion) and (basepeak=C H O+).

Other compounds preparable by the above procedure include: hydroxy 17methyl 8[9 10] abeoestr 4 ene 3,9 dione (M.P.=l76-177 C.) and 1718hydroxy 17m ethinyl 8[9 10] abeo estr-4- ene-3,9-dione (M.P.=234-235C.).

EXAMPLE II 3,17fl-dihydroxy-8 [9 10] -abeo-estra-3,5-diene- 9-onediacetate One and two-fifths grams of 17fl-hydroxy-8[9 10]-abeo-estr-4-ene-3,9-dione were added to a preheated solution (90 C.) of24 ml. of acetic anhydride containing 12 ml. of acetyl chloride and 0.42ml. of pyridine. The solution was stirred for 1 hour at 90 C., and thenquenched by pouring into 300 ml. of an ice-water mixture. 3,1713dihydroxy 8[9+ 10] abeo estra 3,5 diene- 9-one diacetate produced by theabove reaction was isolated by filtration and recrystallized from anether-pentane (3:1) solvent mixture. The compound had the followingcharacteristics Infra-red spectrum: maxima at I: 1690 cm.- 1725 cm.- and1750 cm.- (carbonyl).

Ultra-violet spectrum:

XE2F=235 (6: 15,500)

Other compounds preparable by the process of this invention include:

17/3-hydroxy-17a-vinyl-8 [9 10] -abe0-estr-4-ene-3 ,9-

dione;

17/3-hydroxy-17u-ethyl-8 ['9 10] -abeo-estr-4-ene-3,9-

dione;

I claim: 1. A compound of the formula wherein R and R, when takensingly, are chosen from the group pairs consisting of hydrogen andhydroxyl, ethinyl and hydroxyl, vinyl and hydroxyl, methyl and hydroxyl,ethyl and hydroxyl, propyl and hydroxyl, and acetyl and hydrogen andwhen taken together are a carbonyl group.

2. A compound of the formula wherein R and R, when taken singly, arechosen from the group pairs consisting of hydrogen and hydroxyl, ethinyland hydroxyl, vinyl and hydroxyl, methyl and hydroxyl, ethyl andhydroxyl, propyl and hydroxyl, and acetyl and hydrogen and, when takentogether are a carbonyl group, and wherein Ac is a lower alkanoyl group.

3. A process for preparing 8[9 10] -abeo-steroids and their 3enolacylates which comprises irradiating with ultraviolet light acompound of the formula RVR' f3 Ave ,l I

wherein R and R, when taken singly, are chosen from the group pairsconsisting of hydrogen and hydroxyl, ethinyl and hydroxyl, vinyl andhydroxyl, methyl and hydroxyl, ethyl and hydroxyl, propyl and hydroxyl,and acetyl and hydrogen and, when taken together are a carbonyl group,to form an abeo-steroid of the formula wherein R and R are the same asherein above and then treating said compound with an acylating agent toform a compound of the formula wherein R and IR have the same meaning asherein above and wherein Ac is a lower alkanoyl group.

4. A compound according to claim 1, said compound being 17 fl-hydroxy-S[9 10] -abeo-estr-4-ene-3,9-dione.

5. A compound according to claim 2, said compound being 3,175 dihydroxy8[9 10]-abeo-estra-3,5-diene- 9-one diacetate.

References Cited Jeger et al., Helv. Chem. Acta, 51, 1362 (1968).

LORRAINE A. WEINBERGER, Primary Examiner V. GARNER, Assistant ExaminerU.S. Cl. X.R.

204--158 HE; 260232.55 R, 586 H; 424-311, 331

